Brain insulin receptors and IGF-I receptors are similar to their peripheral, non-neural counterparts, being comprised of two alpha subunits and two beta subunits in a heterotetrameric formation. On sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) they have smaller apparent Mrs compared to the peripheral receptors. These unique receptors are phylogenetically and ontogenetically conserved. These unique insulin and IGF-I receptors have been studied in membranes prepared from whole retina, brain, peripheral nerves, as well as from neural-derived cultured cells. Primary cultures of neuronal cells contain unique insulin and IGF-I receptors resembling those of whole brain. Peripheral nerves and glial cells on the other hand contain insulin and IGF-I receptors similar to those found in non-neural tissues. Both insulin and IGF-I receptors on neural tissues undergo autophosphorylation of the beta subunit following binding of the respective ligand to the predominantly extracellular alpha subunit. In addition, this results in stimulation of tyrosine kinase activity. Thus neuronal receptors, despite their differences in structure, are functional, and their presence suggests a role for insulin and IGF-I in the nervous system.